Project Summary As we enter into an era of personalized medicine, it becomes increasingly important to define the factors that confer disease risk and outcome. Since these determinants cannot be easily controlled in human epidemiological studies, genetically-engineered mouse (GEM) strains provide mechanistically-tractable platforms to define the factors underlying disease heterogeneity and translate them to risk assessment tools and treatments. Pediatric low-grade brain tumors (gliomas) represent one such challenging disease with respect to predicting clinical progression, optimizing treatment, and improving neurologic outcome. In the most common inherited cause for pediatric low-grade glioma, neurofibromatosis type 1 (NF1), 15-20% of children develop optic pathway gliomas (OPGs), leading to visual decline in 30-60% of affected individuals. However, it is not currently possible to predict which child with NF1 will develop an OPG or who will experience visual decline or blindness from their tumor. Our ability to identify those children at greatest risk for OPG development and vision loss would provide important clinically-meaningful prognostic information to guide clinical care for a pre-verbal patient population in which accurate visual assessments can be challenging. Recent observations suggest that the specific germline NF1 gene mutation may be one risk factor for OPG development, whereas patient sex influences OPG-associated visual decline. In this regard, children with NF1-associated OPGs are more likely to harbor specific types of germline NF1 gene mutations (5' end frameshift mutations). In addition, we have recently shown that female children and mice with NF1 more frequently experience visual loss from their OPGs. Based on these provocative findings, we hypothesize that the particular germline NF1 gene mutation and gonadal sex hormones are independent risk factors for OPG development and progression, respectively. In this proposal, we aim to critically determine how the specific NF1 gene mutation dictates OPG formation and define the molecular basis for the observed sexually-dimorphic OPG-associated vision loss using a novel series of Nf1 GEM strains and approaches. The resulting outcomes will be leveraged to preclinically evaluate new approaches to identifying children with NF1 at risk for OPG development and vision loss as well as potential alternative therapeutic approaches for attenuating or preventing NF1-OPG-related visual decline.